Progress in Genomic Medicine

Progress in Genomic Medicine: From Research to Clinical Application provides a careful synthesis of the foundations, current trends and translational challenges in genomic medicine, clarifying pathways forward and enabling genomic medicine research and implementation across clinical settings and treatment development. Sections address the history and growth of genetic medicine, with a discussion of key studies in syndrome delineations, inherited diseases, biochemical genetics, and chromosome abnormalities, overview clinical applications made possible through genomic advances, with chapters on DNA sequencing for clinical genetic diagnosis, genotype-phenotype correlations in individuals and across populations, new-born screening for treatable genetic disorders, and more.

In addition, social, ethical and public health aspects of applying genomic technologies are included throughout. Here, Dr. Smith applies her experience and participation in the field, across its major milestones, to put current research, clinical advances, and ongoing questions in context.

Cover image
Title page
Table of Contents
Copyright
Dedication
Preface
Acknowledgments
Epigraph
Part I: History and Growth of Genetic Medicine
Chapter 1. Documentation of units of inheritance and their contribution to phenotype
Abstract
1.1 Rediscovery of the laws of Mendel
1.2 Genes and genetics
1.3 Nucleic acids
1.4 The structure of DNA
1.5 DNA and chromatin
1.6 Applications of studies of chromosomes, genomes, genes, and gene expression to clinical medicine
1.7 Long-read sequencing for detection of genomic variants including structural chromosome abnormalities
1.8 Determination of the significance of structural variants in the genome
1.9 Mosaicism
1.10 Germline mutations
1.11 Genetic mosaicism in inborn errors of immunity
References
Further reading
Chapter 2. Early documentation of inherited disorders through family studies
Abstract
2.1 The Treasury of Human Inheritance
2.2 Ectrodactyly
2.3 Deafness
2.4 Hemophilia
2.5 Achondroplasia
2.6 Color blindness
2.7 Blue sclerotics and fragility of bone
2.8 Hereditary optic atrophy (Leber’s disease)
2.9 Huntington’s chorea
2.10 Duchenne muscular dystrophy
2.11 Determination of genetic causes of specific diseases and family studies
References
Further reading
Chapter 3. Discoveries in physiology, biochemistry, protein, and enzyme studies between 1920 and 1970
Abstract
References
Further reading
Chapter 4. Early translation of biochemical, metabolic, and genetic discoveries into clinical medicine
Abstract
4.1 ABO
4.2 Further information on the ABO blood group system
4.3 Secretor status
4.4 Mapping of the ABO locus to a chromosome
4.5 Rh blood group system
4.6 RHD genotyping
4.7 Chemical analyses and metabolism incorporating information gathered across the decades
References
Further reading
Chapter 5. Advances in methods of genome analyses, nucleotide analyses, and implications of variants
Abstract
5.1 Introduction
5.2 DNA sequencing
5.3 Applications of long-read sequencing
5.4 Sequence variant interpretation
5.5 Additional evidence for digenic or complex inheritance
5.6 Variants in nonprotein coding genomic regions
5.7 Haplotype phasing
5.8 Haplotype analysis
5.9 Long-range sequencing and identification of structural genomic variants leading to disease
5.10 Investigations of chromatin structure and genomic function
5.11 Methylation analyses
5.12 Imprinted genomic regions
5.13 Genetic disorders where analysis of methylation is important
References
Part II: Clinical Applications of Genomic Medicine
Chapter 6. Expansion of use of genome analyses and sequencing in diagnosis of genetic diseases
Abstract
6.1 Measurement toolkit for assessing the clinical utility of whole genome sequencing
6.2 One phenotype many genes
6.3 Genome sequencing in pediatric developmental defects
6.4 Optical DNA mapping in human genome studies
6.5 Transcriptome sequencing
6.6 Imprinting
6.7 Imprinting disorders
6.8 Prader−Willi syndrome and Angelman syndrome
6.9 Silver−Russell syndrome
6.10 GNAS locus
6.11 Epivariations
6.12 Multilocus imprinting disorders
6.13 Chromosomes genomes and sequence
6.14 Structural genomic variants
6.15 Assessment of copy number changes in different conditions and at different life stages
6.16 Prenatal exome sequence analysis
6.17 Deciphering Developmental Disorders Study
6.18 Investigations of causes of recurrent miscarriage
6.19 Sequencing in prenatal diagnosis: noninvasive prenatal testing
References
Further reading
Chapter 7. Improved analyses of regulatory genome, transcriptome and gene function, mutation penetrance, and clinical applications
Abstract
7.1 Introduction
7.2 Regulatory genome, gene expression, phenotype, and variability
7.3 Epigenetic factors relevant to gene expression
7.4 Regulatory circuit: Epimap
7.5 Genotype phenotype axis
7.6 Promoters
7.7 Transcription initiation and promoters
7.8 Transcription factors
7.9 Transcription termination
7.10 Polyadenylation
7.11 Alternate polyadenylation
7.12 The spliceosome
7.13 MicroRNAs and posttranscriptional regulation
7.14 Translation, ribosomes biogenesis, functions, and defects
7.15 Translation of mRNA to proteins and associated defects leading to disease
7.16 tRNAs
7.17 RNA surveillance
7.18 Translation
7.19 Nonsense-mediated decay
7.20 Nonsense mutations and human disease
7.21 Approved RNA targeted therapeutics
7.22 Therapy with short inhibitory RNAs
7.23 MicroRNAs in therapeutic use
7.24 RNA sequencing in diagnosis of genetic diseases
7.25 Penetrance of mutations and modified penetrance
7.26 Variable penetrance of disease due to polymorphisms in regulatory factors
7.27 Penetrance in inherited eye diseases
7.28 Primary immunodeficiency and incomplete penetrance
References
Chapter 8. Standardized phenotype documentation, documentation of genotype phenotype correlations
Abstract
8.1 Phenotype and clinical genetics
8.2 Congenital malformations and syndromes
8.3 Variable phenotypes associated with specific mitochondrial mutations
8.4 Variable genomic abnormalities in individuals with the same phenotype
8.5 Standardized phenotype documentation, documentation of genotype phenotype correlations databases
8.6 Phenome-wide association studies
8.7 Dysmorphology syndromes with overlapping features due to defect in gene products that function in a specific pathway
8.8 Phenotypic defects due to defects in sonic hedgehog signaling pathway
8.9 Fibroblast growth factor signaling pathway
8.10 Fibroblast growth factor receptor defects
8.11 Transforming growth factor beta signaling pathway
8.12 Marfan syndrome 15q21.1 FBN1
8.13 FBN1 mutations, pathogenic, likely pathogenic, Marfan syndrome multiple submitters, without conflicts identified in Clin Var searches
8.14 Connective tissue disorder Ehlers−Danlos syndrome disorders
8.15 DNA methylation episignatures and phenotypic correlations
References
Chapter 9. Expansion of methods of gene editing therapy and analysis of safety and efficacy
Abstract
9.1 Introduction
9.2 Therapies designed to block nucleotides or RNA derived from a specific gene
9.3 Oligonucleotide therapies
9.4 Delivery challenges in oligonucleotide therapies
9.5 Splice mutations and diseases
9.6 Antisense therapies under investigation
9.7 Genomic data leading to therapeutics
9.8 Pluripotent stem cells for investigation of disease manifestations and effects of therapies
9.9 Gene therapy by adding genes
9.10 Gene therapy
9.11 Stem cells and importance in gene therapy
9.12 Gene editing
9.13 Delivery of reagents for editing
9.14 Preclinical and clinical trials
9.15 NIH (National Institutes of Health) somatic cell gene editing program
9.16 Base editing
9.17 Programmable base editing
9.18 Prime editing
9.19 CRISPR-Cas theta
9.20 RNA editing
9.21 Gene therapy in specific diseases
9.22 Molecular analyses and therapies relevant to hearing loss
9.23 Therapy of cystic fibrosis including genetic approaches
References
Further reading
Chapter 10. Public health applications of genetics including newborn screening and documentation of gene environment interactions
Abstract
10.1 Recessive disorders carrier screening in specific populations
10.2 Newborn screening and hemoglobinopathies
10.3 Cystic fibrosis
10.4 Molecular-based therapeutics
10.5 Newborn screening, United States
10.6 Methods
10.7 Newborn screening in other parts of the world
10.8 Expanded carrier screening
10.9 Genetic disorders with high frequency in certain populations
10.10 Genetic disorders with increased frequency in other specific populations
10.11 Porphyrias
10.12 Factor V Leiden
10.13 Population-wide screening of adults
10.14 Hemochromatosis
10.15 Other disorders that illustrate the impact of gene environment interactions
10.16 Human genetic variation and pathogen sensitivity
10.17 Genetic and environmental factors and additional aspects of population screening
References
Further reading
Chapter 11. Analysis of variants associated with abnormal drug responses, genetics, and genomics in drug design
Abstract
11.1 Pharmacokinetics and pharmacodynamics
11.2 Biotransformation of medicinal compounds
11.3 World-wide distribution of genetic polymorphisms in the CYP450 system
11.4 Other factors and processes involved in biotransformation of drugs
11.5 Drug responses, variants, genetic and environmental factors
11.6 Gene variants that are disease causing and are also associated with abnormal drug reactions
11.7 Porphyrias
11.8 Identifying therapeutic targets and developing therapies
11.9 Translation of biomedical observations to treatments and health improvements
11.10 Fragment-based drug discovery
11.11 Monoclonal antibodies as therapeutic agents
11.12 Approaches to target identification and therapeutic design in specific genetic disorders
11.13 Inborn errors of metabolism
11.14 Lysosomal storage diseases and enzyme replacement therapy
11.15 Ceroid lipofuscinoses
11.16 Aminoacidopathies and organic acidemias
11.17 Transporter defects
11.18 Complexities of mitochondrial diseases and explorations of treatments
11.19 New approaches to cancer therapy
References
Further reading
Chapter 12. Genetic and genomic medicine relevance to cancer prevention, diagnosis, and treatment
Abstract
12.1 Introduction
12.2 Genes with germline mutations predisposing to cancer listed in order of frequency
12.3 Gene products with germline mutations that can lead to cancer and function of these products
12.4 Specific syndromes that include the presence of tumors
12.5 Retinoblastoma and RB1
12.6 Germline succinate dehydrogenase gene mutations and cancer predisposition
12.7 Hereditary gastrointestinal cancers
12.8 Germline mutations and developmental origins of cancer
12.9 Osteosarcoma
12.10 Genetic alterations in cancers in children, adolescents, and young adults
12.11 Adult cancers, driver gene mutations, and passenger gene mutations
12.12 DNA damage and repair
12.13 Lymphomas and leukemia
12.14 Myeloid leukemia
12.15 Providing insight into cancer-inducing mechanisms
12.16 Genome sequencing in cancer
12.17 Cell-free DNA analyses in testing for tumors
12.18 Cell-free studies including transcriptome analyses
12.19 Somatic mutations in cancer
12.20 Breast cancer risk genes
12.21 Whole genome sequencing of metastatic solid tumors
12.22 Therapy-related genetic and genomic information: molecular profiling and cancer therapies
12.23 Synthetic lethality
12.24 Cancer immunotherapy
12.25 CAR-T cells
References
Chapter 13. Benefits of the incorporation of genomic medicine in clinical practice
Abstract
13.1 Genetic and genomic studies in congenital anomalies and/or neurodevelopmental anomalies
13.2 Rare disease medicine
13.3 Carrier screening
13.4 Diagnoses and management in disorders with phenotypic abnormalities
13.5 Databases of importance in searching for gene, genotype phenotype correlations
13.6 Genomic studies to guide diagnosis and therapy in epilepsy
13.7 Diagnostic testing for inborn errors of metabolism leading to seizures
13.8 Epilepsies, genetics, mechanisms, and therapy
13.9 Epilepsy genetics, genomics, and relevance to therapy
13.10 Common epilepsies
13.11 Cerebral palsy and genetic factors
13.12 Typical cerebral palsy
13.13 Monoamine neurotransmitter disorders
13.14 Spastic paraplegias and ataxias
13.15 Friedreich ataxia (FRDA)
13.16 Polyglutamine cerebellar ataxias
13.17 Autosomal recessive ataxias
13.18 Spinocerebellar ataxias
13.19 Spinocerebellar ataxias
13.20 Genomic medicine in common diseases in adults
13.21 Polygenic factors leading to hypertension
13.22 Coronary heart disease
13.23 Genetic-guided therapies
13.24 Approaches to determining polygenic risk scores
13.25 Familial hypercholesterolemia
13.26 Undiagnosed diseases and application of genetic and genomic studies
References
Further reading
Chapter 14. Using insights from genomics to increase possibilities for treatment of genetic diseases
Abstract
14.1 Introduction
14.2 Therapy lysosomal diseases
14.3 Neuroimmune disorders, autophagy lysosomes, and treatment
14.4 Mucopolysaccharidosis II (Hunter syndrome)
14.5 Strategies designed to increase the half-life of enzymes used in enzyme replacement strategies being considered in therapy
14.6 Gene-directed treatments
14.7 Hemoglobinopathy treatment including gene therapy
14.8 Gene-directed therapies in clinical trials in hemoglobinopathies
14.9 Hemoglobinopathy treatment through genetic silencing of BCL11A expression using antisense strategy
14.10 Splice mutations and diseases
14.11 Pluripotent stem cells in investigations of disease therapies
14.12 Relevance to protein folding and secondary modifications
14.13 Defects in ossification and mineralization
14.14 Osteogenesis imperfecta treatment
14.15 Ongoing clinical trials related to cell and gene therapy
14.16 Coagulation disorders
14.17 Von Willebrand factor and disease
14.18 Platelet receptors for Von Willebrand factor
14.19 Understanding mechanisms of rare diseases that may lead to therapy
14.20 Trinucleotide repeat disorders: progress toward therapy
14.21 Toward Huntington disease therapy
14.22 Protein clearance
14.23 Polyglutamine cerebellar ataxias
14.24 Duchenne muscular dystrophy
14.25 DMD therapy molecular approaches
14.26 Utrophin
14.27 Spinal muscular atrophy (autosomal recessive proximal muscular atrophy)
14.28 Antisense oligonucleotides in neurodegenerative diseases
14.29 Dynamic mutability of microsatellite repeats
14.30 Ocular gene therapy
References
Further reading
Index

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Progress in Genomic Medicine

From Research to Clinical Application

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Moyra Smith

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